Neurosurgery Department, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Front Immunol. 2020 Jul 16;11:1449. doi: 10.3389/fimmu.2020.01449. eCollection 2020.
Interleukin-34 (IL-34) is a recently discovered cytokine that acts as a second ligand of the colony stimulating factor 1 receptor (CSF1R) in addition to macrophage colony-stimulating factor (M-CSF). Similar to M-CSF, IL-34 also stimulates bone marrow (BM)-derived monocyte survival and differentiation into macrophages. Growing evidence suggests that peripheral BM-derived monocyte/macrophages (BMMO) play a key role in the physiological clearance of cerebral amyloid β-protein (Aβ). Aβ forms are especially neurotoxic and highly associated with Alzheimer's disease (AD). As a ligand of CSF1R, IL-34 may be relevant to innate immune responses in AD. To investigate how IL-34 affects macrophage phenotype in response to structurally defined and stabilized Aβ oligomers and preformed fibrils, we characterized murine BMMO cultured in media containing M-CSF, IL-34, or regimens involving both cytokines. We found that the immunological profile and activation phenotype of IL-34-stimulated BMMO differed significantly from those cultured with M-CSF alone. Specifically, macrophage uptake of fibrillar or oligomeric Aβ was markedly reduced following exposure to IL-34 compared to M-CSF. Surface expression of type B scavenger receptor CD36, known to facilitate Aβ recognition and uptake, was modified following treatment with IL-34. Similarly, IL-34 macrophages expressed lower levels of proteins involved in both Aβ uptake (triggering receptor expressed on myeloid cells 2, TREM2) as well as Aβ-degradation (matrix metallopeptidase 9, MMP-9). Interestingly, intracellular compartmentalization of Aβ visualized by staining of early endosome antigen 1 (EEA1) was not affected by IL-34. Macrophage characteristics associated with an anti-inflammatory and pro-wound healing phenotype, including processes length and morphology, were also quantified, and macrophages stimulated with IL-34 alone displayed less process elongation in response to Aβ compared to those cultured with M-CSF. Further, monocytes treated with IL-34 alone yielded fewer mature macrophages than those treated with M-CSF alone or in combination with IL-34. Our data indicate that IL-34 impairs monocyte differentiation into macrophages and reduces their ability to uptake pathological forms of Aβ. Given the critical role of macrophage-mediated Aβ clearance in both murine models and patients with AD, future work should investigate the therapeutic potential of modulating IL-34 to increase macrophage-mediated Aβ clearance and prevent disease development.
白细胞介素 34（IL-34）是一种新发现的细胞因子，除了巨噬细胞集落刺激因子（M-CSF）外，它还可以作为集落刺激因子 1 受体（CSF1R）的第二配体。与 M-CSF 类似，IL-34 还刺激骨髓（BM）来源的单核细胞存活并分化为巨噬细胞。越来越多的证据表明，外周 BM 来源的单核细胞/巨噬细胞（BMMO）在脑淀粉样β蛋白（Aβ）的生理性清除中起关键作用。Aβ 形式特别具有神经毒性，并且与阿尔茨海默病（AD）高度相关。作为 CSF1R 的配体，IL-34 可能与 AD 中的固有免疫反应有关。为了研究 IL-34 如何影响巨噬细胞表型对结构定义和稳定的 Aβ 低聚物和原纤维的反应，我们对在含有 M-CSF、IL-34 或涉及两种细胞因子的方案中培养的鼠 BMMO 进行了表征。我们发现，与单独用 M-CSF 培养的细胞相比，IL-34 刺激的 BMMO 的免疫学特征和激活表型有显著差异。具体而言，与 M-CSF 相比，在用 IL-34 处理后，纤维状或低聚物 Aβ 的巨噬细胞摄取明显减少。已知促进 Aβ 识别和摄取的 B 型清道夫受体 CD36 的表面表达在 IL-34 处理后发生改变。同样，IL-34 巨噬细胞表达的参与 Aβ 摄取（髓样细胞触发受体 2，TREM2）和 Aβ 降解（基质金属蛋白酶 9，MMP-9）的蛋白水平较低。有趣的是，通过早期内体抗原 1（EEA1）染色观察到的 Aβ 的细胞内区室化不受 IL-34 影响。还定量了与抗炎和促伤口愈合表型相关的巨噬细胞特征，包括过程长度和形态，并且与用 M-CSF 培养的细胞相比，单独用 IL-34 刺激的巨噬细胞在 Aβ 刺激下的过程伸长较少。此外，与单独用 M-CSF 处理或与 IL-34 联合处理的细胞相比，单独用 IL-34 处理的单核细胞产生的成熟巨噬细胞较少。我们的数据表明，IL-34 会损害单核细胞分化为巨噬细胞，并降低其摄取病理性 Aβ 的能力。鉴于巨噬细胞介导的 Aβ 清除在 AD 小鼠模型和患者中的关键作用，未来的工作应研究调节 IL-34 的治疗潜力，以增加巨噬细胞介导的 Aβ 清除并预防疾病发展。
